The idiotype (Id) of the immunoglobulin expressed on malignant B cells is a clonal marker and therefore can serve as a tumor-specific antigen. In a phase II study, we demonstrated that tumor-derived Id protein from follicular lymphoma patients can be formulated into an immunogenic vaccine by conjugation to an exogenous carrier, keyhole-limpet hemocyanin (KLH) and administering together with granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant. This vaccine induced CD8+ T cell responses which lysed autologous tumor in vitro and achieved molecular remissions in patients in first complete remission after standard chemotherapy1. In January 2000, the NCI opened a multi-institutional phase III randomized clinical trial that is scientifically designed to definitively evaluate the question of clinical benefit induced by patient-specific idiotype vaccines in follicular lymphoma patients. Previously untreated advanced stage follicular lymphoma patients are initially treated with a uniform chemotherapy regimen that has produced complete response in the majority of patients to date ( 85%). Approximately six months after the completion of chemotherapy, patients in complete remission or complete remission unconfirmed are treated with either the experimental tumor-specific vaccine (Id-KLH vaccine + GM-CSF) or the control non-specific vaccine (KLH + GM-CSF). The primary end point of this study is to compare the disease-free survival between the experimental and control arms. Secondary end points include the ability of the vaccine to induce molecular CR after standard chemotherapy, vaccine immunogenicity, and overall survival.The study has enrolled 202 patients. Ultimately, the study will randomize a total of 375 patients, 250 to receive Id-KLH + GM-CSF and 125 to receive KLH + GM-CSF. These numbers are sufficient to allow approximately 80% power to detect a difference between DFS curves with initial hazard ratio of 1.0 for the first 8 months (when treatments are expected to be the same in both randomized arms) and then an intended hazard ratio of 2.0 after the first 8 months. This calculation is based on an assumption of intent to treat analysis in which no patients are excluded once randomized, and they are analyzed as randomized. Data from the phase II study which served as the basis of the present ongoing phase III Protocol. 45% of the patients remain in a complete remission with a mean disease-free-survival of > 8.5 years. Other idiotype vaccine studies include a phase II evaluation of Liposomal IL-2/Id vaccine, and phase II idiotype vaccine coupled with allo and auto stem cell transplantation in patients with multiple myeloma. These protocols are closed to accrual but we continue to follow participants for disease-free and overall survival.